The molecular basis of prostate cancer is still poorly understood, and thus identifying and characterizing genes underlying prostate cancer remains an important task. In our preliminary studies, we have identified the ATBF1 transcription factor as a strong candidate for a tumor suppressor gene at the q22 band of chromosome 16 (16q22), one of the most frequently deleted chromosomal regions in prostate cancer (Nature Genetics 2005, in press). We first narrowed the region of deletion at 16q22 to 861-Kb, which contains the ATBF1 gene. We then found that the expression of ATBF1 is at higher levels in normal prostates but is significantly reduced in prostate cancer cells. Furthermore, expression of ATBF1 suppressed cell proliferation or survival. Most notable is that ATBF1 undergoes frequent somatic mutations in human prostate cancer, as 35 mutations of ATBF1 have been detected in 24 of 66 (36%) cancer samples and many of the mutations clearly interrupt ATBF1 function. A 21/24-nucleotide deletion also occurred in the germline of some prostate cancer patients but has not been detected in normal controls. We therefore hypothesize that ATBF1 is a tumor suppressor gene whose loss of function by genomic deletion, mutation, or loss of expression contributes to the development and progression of prostate cancer. This hypothesis is also supported by some published and unpublished studies from other groups. In this proposal, we will further test this hypothesis in four specific aims. First, we will determine if the 21/24-nucleotide deletion of ATBF1 plays a role in human prostate cancer by performing genetic and functional analyses. Second, we will generate a mouse model in which ATBF1 will be specifically knocked out in the prostates of adult mice, and investigate phenotypic alterations resulting from the loss of ATBF1 function. Third, we will examine the role of ATBF1 deletion in prostate cancer in the context of PTEN inactivation, which is also frequently deleted in human prostate cancer. Finally, in aim 4 we will examine if loss of ATBF1 cooperates with loss of NKX3.1 in inducing prostate cancer. The latter is from another frequently deleted chromosomal region in prostate cancer. Completion of these studies will clarify the role of ATBF1 in prostatic carcinogenesis, and will likely present a target that is potentially useful for the diagnosis and prognosis of prostate cancer, as well as for the study of prostate cancer biology.